This project represents the continuation of a longstanding, ongoing and very productive partnership between the Pittsburgh Supercomputing Center (PSC) and D. E. Shaw Research (DESRES). The project's overarching goal is to provide the biomedical research community access to a truly unique supercomputing resource, Anton, designed and developed by DESRES. Anton's performance exceeds that of present general-purpose supercomputer systems by approximately two orders of magnitude, and allows biomedical scientists to conduct routine long timescale molecular dynamics (MD) simulations at an unprecedented scale. Recently, the next-generation Anton 2 architecture was publicly unveiled at the 2014 Supercomputing Conference and, like Anton 1, was awarded the prestigious ACM Gordon Bell Prize. Since October 2010, DESRES has made a 512-node Anton 1 machine available without cost at the PSC for not-for-profit use. This machine can simulate systems with tens of thousands of atoms at rates above 10 s/day - roughly two orders of magnitude greater than typically achieved by state-of-the-art parallel MD simulation packages running on the fastest general-purpose machines. So far 229 research projects by 120 unique PIs have been conducted on this exceptional resource. The range of investigation possible on Anton is as broad as that of the MD research community itself, and includes protein folding, ion channel selectivity and gating, protein-membrane signaling, and drug interactions with proteins, to name but a few. This breadth is reflected in the range of projects that to date have been accomplished on the machine. Use of the Anton at PSC by the scientific community has already resulted in a significant number of important research findings and high impact publications that we believe would not have been possible otherwise. Here, we propose to continue to make an Anton machine available to the biomedical research community. Since the Anton at PSC is the only machine outside of the DESRES lab, this project represents a unique opportunity for scientists to access this resource for conducting the longest timescale MD simulations currently possible. Importantly, in Year 2 of the award we plan to upgrade Anton 1 with a 128-node Anton 2 machine that will provide a significant increase in computational capabilities. As with the current Anton, the Anton 2 machine to be hosted by PSC will be generously made available by DESRES without cost and thus represents a multi-million dollar resource for the biomedical research community for which the PSC is only requesting funds to cover operating expenses, user support, file storage and basic infrastructure costs. This upgrade will provide roughly a 4-fold increase in simulation speed and, importantly, will allow scientists to simulate system sizes of up to 700,000 atoms, compared to the Anton 1 limit of 150,000 atoms. Thus, Anton 2 will provide biomolecular scientists across the nation with unparalleled simulation capabilities, enabling the study of biological hypotheses not otherwise possible.